For successful treatment of cancer patients, one of the most important factors is the early detection. With the development in gene analysis and proteomics, remarkable progress has been made in the identification of molecular markers for diagnosing and predicting specific cancers.
The epithelium-derived cancer refers to a cancer originated from the epithelial cell, and includes but is not limited to breast cancer, gastric cancer, oral cancer, esophageal cancer, colon cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, cervix cancer, lung cancer, breast cancer and skin cancer, prostate cancer, renal cancer and the like.
For example, the gastric cancer is the second-leading cause of death by cancer in the world and one of the most common malignant tumors that threaten the human health. The key of the prognosis of gastric cancer patients is to make a good secondary prophylaxis, i.e. early finding and early treating. The early, timely and accurate detection and treatment of the gastric cancer have an important meaning in reducing the gastric cancer mortality.
Lung cancer is a common lung malignant tumor. In recent years, the morbidity and mortality of lung cancer rapidly increase due to the influences of smoking and various environmental factors in the world, especially in the industrially developed countries. The development of serum tumor markers having a high specificity and sensibility has an important meaning for the early finding and treating of lung cancer.
Molecular diagnosis is the most popular method of diagnosing cancer. Different kinds of molecules such as DNA, protein, and fat are used as diagnosis tools. Tumor markers (TM) refer to a group of substances that are produced or secreted by tumor cells and released into blood, cells and body fluid in the process of tumorigenesis and proliferation, which reflect the presence and growth of tumors. Tumor markers are generally proteins, and are widely used in the detection and diagnosis of various types of cancers. The increase of tumor marker concentration may indicate that a cancer is present in the human body in a certain form. Tumor markers are clinically used in the finding of primary tumors, the screening of tumor high risk population, the differential diagnosis of benign and malignant tumors, the determination of tumor development level, the observation and evaluation of tumor therapeutic effect, the predicting of tumor relapse and prognosis, and the like. Tumor markers are generally measured by immunoassay methods, such as indirect method, double antibody sandwich method, and competitive method. The detection methods include colloidal gold method, enzyme-linked immunosorbent assay, chemiluminescent assay, electrochemiluminescence assay and the like. The object of serological detection is to determine the contents of cancer-related tumor markers in patient's serum. This method is simple and practicable, and therefore is suitable for the extensive survey in a large population. For example, the gastric cancer-related tumor markers that are currently widely used internationally include CEA, TPS and CA72-4, and the like.
Cytokeratins include over 20 different proteins, and are important constituents of cytoskeleton. Although all of the cells with an epithelium origin express a certain level of cytokeratin, certain constituents of keratin such as keratins 8, 18 and 19 have an intimate relationship with the genesis and development of malignant tumors (M. Nap, Th. Van Wel, C. Andres, et al. Immunohistochemical Profiles of 30 Monoclonal Antibodies against Cytokeratins 8, 18 and 19[J]. Tumor Biology 2001; 22:4-10).
Cytokeratin 18 is an acidic protein having a molecular weight of 55 kD, consists of 430 amino acids, has a highly conservative center region with an alpha helix structure, and shows a filament-like structure. It is widely distributed in normal tissue surfaces, such as stratified epithelium and squamous epithelium, and monolayer epithelial cells such as acinus, trachea, mammary duct, sweat gland, endometrium, colon and hepatic cell. In normal epithelial cells, the expression of cytokeratin 18 is relatively stable. There is no or low expression of cytokeratin 18 and its fragments in peripheral blood, marrow, and lymph node. Almost no fragments are released into blood. On the contrary, in case of malignant transformation of epithelial cells, the expression of cytokeratin 18 sharply increases. In the meanwhile, the growth of cytokeratin 18 becomes abnormal. The protease activated in the apoptosis and necrosis of tumor cells accelerates cell degradation, which allows many soluble cytokeratin 18 fragments to be released, and causes the concentration of soluble cytokeratin 18 fragments in tissue fluid and body fluid (in particular in the blood circulation of patients having gastric cancer) to increase (Stig L, Aleksandra M H, Takayuki U, et al. Determining tumor apoptosis and necrosis in patient serum using cytokeratin 18 as a biomarker[J]. Cancer Letters 214 (2004):1-9; T. Stigbrand. The Versatility of Cytokeratins as Tumor Markers[J]. Tumor Biology 2001; 22:1-3).
Cytokeratin 19 is an acidic protein having a molecular weight of 40 kD, the smallest member in the keratin family, consists of 400 amino acids, has a highly conservative center region with an alpha helix structure, and shows a filament-like structure. It is widely distributed in normal tissue surfaces, such as stratified epithelium and squamous epithelium, and monolayer epithelial cells such as acinus, trachea, mammary duct, sweat gland, endometrium, colon and hepatic cell. In normal epithelial cells, the expression of cytokeratin 19 is relatively stable. There is no or low expression of cytokeratin 19 and its fragments in peripheral blood, marrow, and lymph node. Almost no fragments are released into blood circulation system. On the contrary, in case of malignant transformation of epithelial cells, the expression of cytokeratin 19 sharply increases. In the meanwhile, the growth of cytokeratin 19 becomes abnormal. The protease activated in the apoptosis and necrosis of tumor cells accelerates cell degradation, which allows many soluble cytokeratin 19 fragments to be released, and causes the concentration of the soluble cytokeratin 19 fragments in tissue fluid and body fluid (in particular in blood circulation of patients having lung cancer) to increase (J. Niklinski, T. Burzykowski, W. Niklinska, et al. Preoperative CYFRA 21-1 level as a prognostic indicator in resected nonsmall cell lung cancer [J]. Eur Respir J 1998; 12: 1424-1428).